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Review
, 17 (6)

Tetrapyrroles as Endogenous TSPO Ligands in Eukaryotes and Prokaryotes: Comparisons With Synthetic Ligands

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Review

Tetrapyrroles as Endogenous TSPO Ligands in Eukaryotes and Prokaryotes: Comparisons With Synthetic Ligands

Leo Veenman et al. Int J Mol Sci.

Abstract

The 18 kDa translocator protein (TSPO) is highly 0conserved in eukaryotes and prokaryotes. Since its discovery in 1977, numerous studies established the TSPO's importance for life essential functions. For these studies, synthetic TSPO ligands typically are applied. Tetrapyrroles present endogenous ligands for the TSPO. Tetrapyrroles are also evolutionarily conserved and regulate multiple functions. TSPO and tetrapyrroles regulate each other. In animals TSPO-tetrapyrrole interactions range from effects on embryonic development to metabolism, programmed cell death, response to stress, injury and disease, and even to life span extension. In animals TSPOs are primarily located in mitochondria. In plants TSPOs are also present in plastids, the nuclear fraction, the endoplasmic reticulum, and Golgi stacks. This may contribute to translocation of tetrapyrrole intermediates across organelles' membranes. As in animals, plant TSPO binds heme and protoporphyrin IX. TSPO-tetrapyrrole interactions in plants appear to relate to development as well as stress conditions, including salt tolerance, abscisic acid-induced stress, reactive oxygen species homeostasis, and finally cell death regulation. In bacteria, TSPO is important for switching from aerobic to anaerobic metabolism, including the regulation of photosynthesis. As in mitochondria, in bacteria TSPO is located in the outer membrane. TSPO-tetrapyrrole interactions may be part of the establishment of the bacterial-eukaryote relationships, i.e., mitochondrial-eukaryote and plastid-plant endosymbiotic relationships.

Keywords: TSPO; TSPO binding site structures; TSPO ligand binding; cell function; eukaryotes; homeostasis; life expectancy; prokaryotes; stress; tetrapyrrole.

Figures

Figure 1
Figure 1
Overview of the subject of this review. Endogenous ligands (tetrapyrroles) as well as synthetic ligands for translocator protein (TSPO) affect functions of free living prokaryotes as well as the derived endosymbionts present as mitochondria and plastids in eukaryotes. A few of these functions modulated by TSPO and its ligands are listed on the right-hand side.
Figure 2
Figure 2
This figure presents line drawings of the molecular structures of seven known TSPO ligands (listed in the most left hand column), to visualize for each one the structural compatibilities of the synthetic ligands with the molecular structure of other synthetic ligands and the endogenous TSPO ligand PPIX. For orientation in the figure, adjacent to each molecular structure the letter refers to the row (lined up with the compound's name) and the numbers refer to the columns related to the molecular structure characteristics (i.e., 1 relates to Molecular Structure, 2 relates to Reoriented Molecular Structure, and 3 relates to Compatibility to PPIX structure). These TSPO ligands were first described as such by: Verma et al. [8] (PPIX), Le Fur et al. [44] (Ro5-4864 and PK 11195), Vainshtein et al. [22] (2-Cl-MGV-1), Romeo et al. [45] (FGIN-1-27), Denora et al. [46] (CB86 and CB256). Their full names at the left hand beginnings or their rows are, respectively : 3-[18-(2-carboxyethyl)-8,13-bis(ethenyl)-3,7,12,17-tetramethyl-22,23-dihydroporphyrin-2-yl]propanoic acid (protoporphyrin IX ; abbreviation PPIX in row A), 7-chloro-5-(4-chlorophenyl)-1-methyl-3H-1,4-benzodiazepin-2-one (Ro5-4864 in row B); 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide (PK 11195 in row C); [2-(2-chlorophenyl)quinazolin-4-yl dimethylcarbamate] (2-Cl-MGV-1 in row D); N,N-di-n-hexyl 2-(4-fluorophenyl)indole-3-acetamide (FGIN-1-27 in row E); 2-(8-amino-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)-N,N-dipropylacetamide (CB86 in row F) 2-(8-(2-(bis(pyridin-2-yl)methyl)amino)acetamido)-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)-N,N-dipropylacetamide (CB256 in row G). In the first, left hand column the names of the ligands are given as they are generally used in the scientific community (not numbered here). In the second column (indicated with #1) the molecular structures are given as they are typically presented in the literature. In the third column (indicated with #2) the molecular structures are reoriented to facilitate visualization of a potential match with a corresponding part of PPIX. This reorientation typically is no more than flipping and rotating the original drawing, if required at all. Regarding the drawing of “CB256”, rotations of several bonds are applied (using ChemBioDraw™) to achieve a configuration that matches the structure of PPIX. In the fourth, most right handed column (indicated with #3), in each row, the PPIX molecular structure is presented. In this fourth column, for each row, angular shapes are drafted, outlining the parts of PPIX that may potentially correspond to the full molecular structures of the ligands in the rows in question. Thus, this figure presents structural characteristics common to various TSPO ligands. One can assume that the structural commonalities are related to shared functions (as well as affinity for the TSPO), while the structural differences may be related to differences in effects (as well as differences in affinity for the TSPO). The molecular structures were drawn with the aid of ChemBioDraw ™ of PerkinElmer, 940 Winter Street, Waltham, MA, USA.
Figure 2
Figure 2
This figure presents line drawings of the molecular structures of seven known TSPO ligands (listed in the most left hand column), to visualize for each one the structural compatibilities of the synthetic ligands with the molecular structure of other synthetic ligands and the endogenous TSPO ligand PPIX. For orientation in the figure, adjacent to each molecular structure the letter refers to the row (lined up with the compound's name) and the numbers refer to the columns related to the molecular structure characteristics (i.e., 1 relates to Molecular Structure, 2 relates to Reoriented Molecular Structure, and 3 relates to Compatibility to PPIX structure). These TSPO ligands were first described as such by: Verma et al. [8] (PPIX), Le Fur et al. [44] (Ro5-4864 and PK 11195), Vainshtein et al. [22] (2-Cl-MGV-1), Romeo et al. [45] (FGIN-1-27), Denora et al. [46] (CB86 and CB256). Their full names at the left hand beginnings or their rows are, respectively : 3-[18-(2-carboxyethyl)-8,13-bis(ethenyl)-3,7,12,17-tetramethyl-22,23-dihydroporphyrin-2-yl]propanoic acid (protoporphyrin IX ; abbreviation PPIX in row A), 7-chloro-5-(4-chlorophenyl)-1-methyl-3H-1,4-benzodiazepin-2-one (Ro5-4864 in row B); 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide (PK 11195 in row C); [2-(2-chlorophenyl)quinazolin-4-yl dimethylcarbamate] (2-Cl-MGV-1 in row D); N,N-di-n-hexyl 2-(4-fluorophenyl)indole-3-acetamide (FGIN-1-27 in row E); 2-(8-amino-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)-N,N-dipropylacetamide (CB86 in row F) 2-(8-(2-(bis(pyridin-2-yl)methyl)amino)acetamido)-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)-N,N-dipropylacetamide (CB256 in row G). In the first, left hand column the names of the ligands are given as they are generally used in the scientific community (not numbered here). In the second column (indicated with #1) the molecular structures are given as they are typically presented in the literature. In the third column (indicated with #2) the molecular structures are reoriented to facilitate visualization of a potential match with a corresponding part of PPIX. This reorientation typically is no more than flipping and rotating the original drawing, if required at all. Regarding the drawing of “CB256”, rotations of several bonds are applied (using ChemBioDraw™) to achieve a configuration that matches the structure of PPIX. In the fourth, most right handed column (indicated with #3), in each row, the PPIX molecular structure is presented. In this fourth column, for each row, angular shapes are drafted, outlining the parts of PPIX that may potentially correspond to the full molecular structures of the ligands in the rows in question. Thus, this figure presents structural characteristics common to various TSPO ligands. One can assume that the structural commonalities are related to shared functions (as well as affinity for the TSPO), while the structural differences may be related to differences in effects (as well as differences in affinity for the TSPO). The molecular structures were drawn with the aid of ChemBioDraw ™ of PerkinElmer, 940 Winter Street, Waltham, MA, USA.
Figure 3
Figure 3
This scheme very concisely summarizes evolutionary relations between bacteria and eukaryotes regarding the presence of TSPO in these life forms, as well as the associated functions. In particular, it appears that during evolution, originally free living bacteria with TSPO became part of eukaryotes in the form of organelles, such as mitochondria and plastids with TSPO. In eukaryotes the TSPO functions that can be found in bacteria appear to basically have been maintained in cellular organelles. Beyond this, in prokaryotes as well eukaryotes, including multicellular organisms, TSPO serves to maintain homeostasis and viability.

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